Unsaturated fatty acids, particularly the essential fatty acids (EFAs), shown in Table I below and certain others, have a range of possible medical uses.
Besides the essential fatty acids, there are more particularly oleic acid, parinaric acid and other fatty acids with conjugated double bonds, and columbinic acid, a fatty acid with non-conjugated bonds which, while not being an essential fatty acid, can correct many of the features of essential fatty acid deficiency. Parinaric acid is an 18:4 n-3 acid (9 cis, 11 trans, 13 trans, 15 cis); columbinic acid is an 18:3 n-6 acid (6, 9 cis, 13 trans).
The bodily conversions of the main series of EFAs appear in the table, which is:
TABLE 1 __________________________________________________________________________ n-6 n-3 __________________________________________________________________________ 18:2 delta-9, 12 18:3 delta-9, 12, 15 (linoleic acid) (alpha-linolenic acid) .vertline. delta-6 desaturase .dwnarw. 18:3 delta-6, 9, 12 18:4 delta-6, 9, 12, 15 (gamma-linolenic acid) (stearidonic acid) .vertline. elongation .dwnarw. 20:3 delta-8, 11, 14 20:4 delta-8, 11, 14, 17 (dihomo-gamma-linolenic acid) .vertline. delta-5 desaturase .dwnarw. 20:4 delta-5, 8, 11, 14 20:5 delta-5, 8, 11, 14, 17 (arachidonic acid) (`eicosapentaenoic acid`) .vertline. elongation .dwnarw. 22:4 delta-7, 10, 13, 16 22:5 delta-7, 10, 13, 16, 19 (adrenic acid) .vertline. delta-4 desaturase .dwnarw. 22:5 delta-4, 7, 10, 13, 16 22:6 delta-4, 7, 10, 13, 16, 19 (`docosahexaenoic acid`) __________________________________________________________________________
The above pathways are not normally reversible nor, in man, are n-3 and n-6 series acids inter-convertible.
The acids, which in nature are of the all-cis configuration, are systematically named as derivatives of the corresponding octadecanoic, eicosanoic or docosanoic acids, e.g. delta-9, 12 octadecadienoic acid or delta-4, 7, 10, 13, 16, 19-docosahexaenoic acid, but numerical designations such as, correspondingly, 18:2 n-6 or 22:6 n-3 are convenient. Initials, for example, EPA for the 20:5 n-3 acid (eicosapentaenoic acid) or DHA for the 22:6 n-3 acid (docosahexaenoic acid), are also used but do not serve when n-3 and n-6 acids of the same chain length and degree of unsaturation exist as for example with the 22:5 acids. Trivial names in more or less common use in the n-6 series are as shown. Of the n-3 series only 18:3 n-3 has a commonly used trivial name, alpha-linolenic acid, though the name stearidonic acid is coming into use for the 18:4 n-3 acid and the names eicosapentaenoic acid and docosahexaenoic acid as such are also used. The alpha isomer of linolenic acid was characterised earlier than gamma-linolenic acid and reference in the literature simply to linolenic acid, especially in the earlier literature, is to the alpha-acid.
Many of these fatty acids have actions which appear synergistic with one another. For example, gamma-linolenic acid (GLA) exerts one set of anti-inflammatory effects while eicosapentaenoic acid (EPA) exerts another set of anti-inflammatory effects. Many of the fatty acids are easily oxidised, while oleic acid exerts potent anti-oxidant effects. Arachidonic acid (AA) is an important constituent of cell membranes but can be harmful if converted to pro-inflammatory, pro-thrombotic and vasoconstrictor metabolites, such as thromboxne A.sub.2 or leukotrienes: it is therefore useful to administer AA with a fatty acid which reduces its conversion to the harmful metabolites.
In most countries further, the guidelines for pharmaceutical products militate against ready acceptance of drugs which are mixtures of compounds, such as mixtures of fatty acids. It is therefore preferable to seek approval for single molecules.
It would therefore be desirable to have a vehicle, for administration of fatty acids, incorporating different fatty acids in the form of a single molecule, and we propose the use of phospholipids such as P-serine, P-choline, P-ethanolamine, or P-inositol (P-phosphotidyl), which have two sites at which fatty acids may be incorporated. Such phospholipids are close to the natural phospholipids and are therefore appropriate single molecules for delivery of two different fatty acids.